This invention relates to the inhibition of arterial thrombotic occlusion or thromboembolism by plasma-derived or recombinant produced activated protein C (APC) alone or in combination with a thrombolytic agent.
Many of the surgical procedures carry the risk of venous and arterial thrombosis and thromboembolism. Application of current anti-platelet or fibrinolytic drugs in intraoperative or postoperative cases could lead to serious bleeding complications. Thus, the use of these agents requires extra precaution. Even in diseases complicated with arterial thrombosis, the use of antithrombotic and/or thrombolytic therapy has undesired side effects, such as bleeding or reocclusion during thrombolytic treatment in myocardial infarction, bleeding or thrombosis following surgery, and thrombosis following surgery that employs grafts or other cardiovascular prosthetic devices.
Therefore, there is a need for an antithrombotic therapy which would be anticoagulant, anti-platelet and fibrinolytic at the same time without the hazards of hemorrhage. APC is unique among the physiologic anticoagulants since it inhibits coagulation and stimulates fibrinolysis. APC inhibits the thrombin mediated activation of platelets as well as the formation of fibrin, and thus, the formation of arterial thrombus built up mostly by platelets and fibrin. The use of APC reduces the dose of tissue-type plasminogen activator (t-PA) or other thrombolytic agents by its actions. Thus, APC provides safer thrombolysis with less risk of bleeding and less risk of reocclusion.
APC is a potent anticoagulant enzyme in vitro and in vivo. APC inhibits the blood coagulation pathways and the formation of thrombin by proteolytic cleavage of F.Va and F.VIIIa, and also enhances fibrinolysis (Seegers et al., Thrombosis Res., 1, 443-460 (1972); Kisiel, J. Clin. Invest., 64, 761-769 (1979); Marlar & Griffin, J. Clin. Invest., 66, 1186-1189 (1980); Marlar et al., Blood, 59, 1067-1072 (1982); Clouse & Comp, New Engl. J. Med., 314, 1298-1304 (1986)). APC is generated from its circulating precursor, namely from the vitamin K dependent protein C (PC), upon activation by immobilized thrombin on the endothelium of blood vessels (Mammen et al., Thromb. Diath. Haemorrh., 5, 218-249 (1960); Stenflo, J. Biol. Chem., 251, 355-363 (1976); Esmon & Owen, Proc. Natl. Acad. Sci. USA, 78, 2249-2252 (1981)). APC, through the protein C pathway, serves as the enzyme central to the negative feedback regulation of coagulation. Inherited deficiency in PC is associated with venous thromboembolic diseases (Griffin et al., J. Clin. Invest., 68, 1370-1373 (1981); Bertina et al., Thromb. Haemost., 48, 1-5 (1982); Griffin, Seminars in Thrombosis and Hemostasis, 10, 162-166 (1984); Marciniak et al., Blood, 65, 15-20 (1985)), but inherited protein C deficiency is not significantly associated with arterial thrombosis (Coller et al., Arteriosclerosis, 7, 456-462 (1987). Infusion of APC decreases blood coagulability in various animal models and prevents the coagulopathic and lethal effects in E. coli infusion in baboons (Comp & Esmon, J. Clin. Invest., 68, 1221-1228 (1981); Comp et al. , J. Clin. Invest., 70, 127-134 (1982); Colucci et al., J. Clin. Invest., 74, 200-204 (1984); Taylor et al., J. Clin. Invest., 79, 918-925 (1987); Burdick & Schaub, Thrombosis Res., 45, 413-419 (1987)). Infusion of a thrombolytic agent like t-PA into humans results in effective thrombolysis in acute myocardial infarction (AMI) (Yusuf et al., European Heart Journal, 6, 556-585 (1985); European Cooperative Study Group, Lancet., 842-847 (1985)).